This invention relates to novel aerosol formulations for administering drugs, in particular for administration of a beclomethasone ester by inhalation.
Beclomethasone dipropionate is 9.alpha.-chloro-16.beta.-methyl-1,4-pregnadiene-11.beta., 17.alpha.,21-triol-3,20-dione 17.alpha.,21-dipropionate and may be represented by the formula (I) ##STR1## The corticosteroid of formula (I) is known to exhibit topical antiinflammatory activity and is useful in the treatment of asthmatic conditions, particularly in the form of aerosol formulations. The use of such formulations is described in GB-1429184 where it is noted that micronised anhydrous beclomethasone dipropionate tends to display crystal growth, due to solvate formation, when incorporated into aerosol formulations containing chlorofluorocarbon propellants. Crystals having a particle size of more than 20 microns were shown to be too large to penetrate the bronchial system and prone to cause clogging of the metering valve making them unsuitable for administration by inhalation.
A number of potential solutions to this problem have been proposed. These include the use of micronised solvates of beclomethasone dipropionate, for example chlorofluorocarbon solvates (GB-1429184), ethyl acetate solvate (DE-3018550OS), C.sub.5-8 alkane solvates (EP-0039369), diisopropyl ether solvate (EP-0172672) and C.sub.1-5 alcohol solvates (WO86/03750). GB-2076422A discloses a process for the preparation of chlorofluorocarbon aerosols which incorporates a low temperature (5 to -40.degree. C.) step which is also claimed to inhibit crystal growth.
An alternative solution to the problem of crystal growth in aerosol formulations containing beclomethasone dipropionate has recently been disclosed in WO92/06675. This document describes the preparation of aerosol formulations containing solutions of beclomethasone diproprionate in ethanol, together with hydrofluorocarbon 134a (1,1,1,2-tetrafluoroethane) or hydrofluorocarbon 227 (1,1,1,2,3,3,3-heptafluoropropane) as propellant. Since a solution of beclomethasone dipropionate in ethanol is employed in the aerosols rather than a suspension of particulate beclomethasone diproprionate, elaborate process steps or the preparation of a solvate of the active ingredient prior to incorporation into the aerosol formulation is not required.
Nevertheless, whilst ethanol is pharmaceutically acceptable and generally recognised as safe, it is associated with a number of disadvantages which may restrict is use. In particular, administration of ethanol-containing products to teetotal or alcohol-dependent individuals or to children is undesirable.
A number of other patent applications describe the preparation of aerosol formulations containing drug and a fluorocarbon propellant, together with the addition of one or more adjuvants such as surfactants. Thus, for example WO91/14422 describes the preparation of aerosol formulations containing beclomethasone dipropionate in the form of its 1,1,1,2-tetrafluoroethane clathrate together with 1,1,1,2-tetrafluoroethane and various surface-active dispersing agents.
We have now found that certain novel aerosol formulations containing particulate beclomethasone diproprionate are surprisingly stable without recourse to the use of any adjuvant or cosolvent in the composition.